We propose that the human immune system cannot react to HIV-1 infection with a robust, protective antibody response because of the inherent processes by which such responses develop and because the tertiary and quaternary structure of the HIV-1 Env obscures neutralizing epitopes until the virion Env is in direct proximity to its target ligands. Our first hypothesis states that in order for human antibodies to strongly and successfully protect from infection or control active infection, antibodies must function in an integrative fashion. One class of antibodies must be produced that bind to Env expressed on native virion and expose neutralizing epitopes for a second class of neutralizing antibodies. Our second hypothesis stages that because of the inherent process by which antibodies are selected, an inappropriate isotype response to trimeric HIV-1 Env is made; more flexible antibody isotypes, such as IgG3, would be more effective in both processes defined in our first hypothesis. We have developed a virus capture assay that measures antibody binding to intact whole virus, and a double-antibody capture assay that permits the study of epitope exposure on intact virions by soluble phase binding of single or multiple antibodies or sera, and subsequent capture by solid phase antibodies. We have also developed systems for isotype switching Human Monoclonal Antibodies (HMAb) to IgG1, IgG3 or IgA isotypes which can be tested in these systems. We have shown, in our preliminary studies that infected humans make a limited antibody response to intact Primary Isolate (PI) virions and identified unique HMAb that bind PI virions. We now propose to extend our experiments to study capture, exposure, and neutralization by sera and HMAb: quantifying binding to intact virions; assessing neutralization; and studying exposure of neutralizing epitopes and the integration of antibody responses and binding. Plasma/sera will also be studied for the relative efficacy of different isotypes to mediate capture, exposure and neutralization, and selected HMAb will be isotype switched to IgG3 and IgA isotypes, produced and studied for the effect of isotype on these parameters. We will also study long term non-progressors and early progressors to assess the relationship of antibody to intact PI virions to control of disease as a basis for larger more powerful evaluations.